An Integrated Epigenomic and Genomic View on Phyllodes and Phyllodes-like Breast Tumors

SIMPLE SUMMARY: Fibroepithelial tumors of the breast represent a spectrum of mostly benign diseases. However, some of these tumors tend to recur and may even spread distantly to other body sites. Prediction of their biological behavior is currently morphology-centered. In this study, we set out to answer the question of whether their biologic behavior might be reflected by specific DNA methylation and copy number profiles, both of which can be determined alongside each other in a diagnostic routine workflow through microarrays. We discovered that the fibroepithelial tumors seem to fall into two distinct copy number variant patterns and that they are epigenetically related. Our study underlines the diagnostic usefulness of combined methylation/copy number profiling in fibroepithelial breast tumors to predict clinical outcomes. ABSTRACT: Fibroepithelial lesions (FL) of the breast, in particular, phyllodes tumors (PT) and fibroadenomas, pose a significant diagnostic challenge. There are no generally accepted criteria that distinguish benign, borderline, malignant PT and fibroadenomas. Combined genome-wide DNA methylation and copy number variant (CNV) profiling is an emerging strategy to classify tumors. We compiled a series of patient-derived archival biopsy specimens reflecting the FL spectrum and histological mimickers including clinical follow-up data. DNA methylation and CNVs were determined by well-established microarrays. Comparison of the patterns with a pan-cancer dataset assembled from public resources including “The Cancer Genome Atlas” (TCGA) and “Gene Expression Omnibus” (GEO) suggests that FLs form a methylation class distinct from both control breast tissue as well as common breast cancers. Complex CNVs were enriched in clinically aggressive FLs. Subsequent fluorescence in situ hybridization (FISH) analysis detected respective aberrations in the neoplastic mesenchymal component of FLs only, confirming that the epithelial component is non-neoplastic. Of note, our approach could lead to the elimination of the diagnostically problematic category of borderline PT and allow for optimized prognostic patient stratification. Furthermore, the identified recurrent genomic aberrations such as 1q gains (including MDM4), CDKN2a/b deletions, and EGFR amplifications may inform therapeutic decision-making.